Glioblastoma Multiforme (GBM), the most common brain cancer of adults, is among the most aggressive and deadly of neoplasm (WHO grade IV), and is accounted for more than 21% of all primary brain and CNS tumors. The annual incidence of GBM in the United States is 3.01 per 100,000 and is an incurable cancer with a median survival of approximately 12 months from diagnosis. Despite decades of intensive surgical treatment, chemotherapy, radiotherapy, and tremendous basic science and clinical research focused on combating this disease, the prognosis remains virtually unchanged, with survival rates still measured in months. The current genetic understanding of GBM has led to the identification of crucial intracellular molecules and their associated signaling pathways as potential therapeutic targets. We are taking the advantage of RNA interference (RNAi) technology for development of the targeted therapeutics. Three small interfering RNA (siRNA) cocktails targeting EGFR-VEGF-AGT, or EGFR-VEGF-MMP9, or EGFR-VEGF-TGF respectively, will be packaged with Histidine and Lysine polymer (HKP) and Saposin C DOPS liposome nanoparticles for treatment of GBM. The antitumor efficacy of these siRNA nanoparticle drugs will be evaluated with human glioma cell lines U87 and murine glioma cells SMA-560 cell tumor models. We will also characterize the HKP and SapC-DOPS nanoparticle systems with the most potent siRNA cocktail and selected a nanoparticle-siRNA cocktail formulation for GBM treatment with the favorable efficacy and safety profile. Lastly, we will evaluate combined regimen of the siRNA cocktail A with TMZ, or cocktail B and C with Avastin, using the U87 and SMA-560 cell tumor models, with the best nanoparticle delivery formulation. A novel therapeutic protocol will be ready for further preclinical study to support a Phase II grant application. PUBLIC HEALTH RELEVANCE: Glioblastoma Multiforme (GBM), the most common brain cancer of adults, is among the most aggressive and deadly of neoplasm (WHO grade IV), and is accounted for more than 21% of all primary brain and CNS tumors. The annual incidence of GBM in the United States is 3.01 per 100,000 and is an incurable cancer with a median survival of approximately 12 months from diagnosis. Despite decades of intensive surgical treatment, chemotherapy, radiotherapy, and tremendous basic science and clinical research focused on combating this disease, the prognosis remains virtually unchanged. We are proposing here to take the advantage of RNA interference (RNAi) technology for development of a novel targeted therapeutic with three small interfering RNA (siRNA) cocktails targeting EGFR-VEGF-AGT, or EGFR-VEGF-MMP9, or EGFR-VEGF-TGF respectively. Two nanoparticle systems, HKP and SapC-DOPS, will be applied with the most potent siRNA cocktail and in combination with the small molecule antagonist drug (TMZ) and monoclonal antibody drug (Avastin) for their antitumor efficacy using both xenograft (U87 cell) and syngeneic (SMA-560 cell) mouse tumor models.